Genetic Rodent Models of Amyotrophic Lateral Sclerosis

L. Van Den Bosch

doi:10.1155/2011/348765

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective death of motor neurons in the motor cortex, brainstem, and spinal cord. A large number of rodent models are available that show motor neuron death and a progressive motor phenotype that is more or less reminiscent of what occurs in patients. These rodent models contain genes with spontaneous or induced mutations or (over) express different (mutant) genes. Some of these models have been of great value to delineate potential pathogenic mechanisms that cause and/or modulate selective motor neuron degeneration. In addition, these genetic rodent models play a crucial role in testing and selecting potential therapeutics that can be used to treat ALS and/or other motor neuron disorders. In this paper, we give a systematic overview of the most important genetic rodent models that show motor neuron degeneration and/or develop a motor phenotype. In addition, we discuss the value and limitations of the different models and conclude that it remains a challenge to find more and better rodent models based on mutations in new genes causing ALS.

Highlights

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the motor cortex, brainstem, and spinal cord
For more than a decade, the mutant SOD1 mice and rats have been the prototype of an ideal model to study motor neuron death, the hallmark of ALS
The major frustration is that this almost perfect model did not lead to a major breakthrough on the therapeutic level

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the motor cortex, brainstem, and spinal cord. FALS and SALS are clinically indistinguishable, and all patients experience muscle weakness, atrophy, and spasticity This is the consequence of the loss of both upper and lower motor neurons. All other genetic causes of FALS are rare and/or cause an atypical form of ALS These include mutations in the genes encoding alsin (ALS2; [12]), senataxin (ALS4; [13]), spatacsin (ALS5; [14]), vesicle-associated membrane protein B (VAPB; ALS8; [15]), angiogenin (ALS9; [16]), optineurin (ALS12; [17]), and dynactin [18]. (rare) sequence variants in a number of other genes were reported to be associated with ALS These variations were found in candidate genes or through genome wide association studies [2]. We will give a systematic overview of the most important rodent models that show motor neuron degeneration and discuss the value and limitations

Spontaneous or Induced Motor Neuron Degeneration in Mice

Rodent Models of Typical Mendelian FALS

Rodent Models of Atypical or Rare Mendelian FALS

Rodent Models Based on Candidate Genes

Findings

Conclusions